KEGG   DISEASE: H00058Help
Entry
H00058                      Disease                                

Name
Amyotrophic lateral sclerosis (ALS);
Lou Gehrig's disease
Description
Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial ALS (FALS) cases, is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS). Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess increases intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions , which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, affecting axonal transport. Collectively, these mechanisms are predicted to disturb cellular homeostasis, ultimately triggering motor neuron death.
Category
Neurodegenerative disease
BRITE hierarchy
Pathway
Amyotrophic lateral sclerosis (ALS)
Gene
(ALS1) SOD1; superoxide dismutase (mutation) [HSA:6647] [KO:K04565]
(ALS2) ALS2; alsin (mutation) [HSA:57679] [KO:K04575]
(ALS4) SETX; senataxin (mutation) [HSA:23064] [KO:K10706]
(ALS6) FUS; fusion (mutation) [HSA:2521] [KO:K13098]
(ALS8) VAPB; VAMP-associated protein (mutation) [HSA:9217] [KO:K10707]
(ALS9) ANG; angiogenin (mutation) [HSA:283] [KO:K16631]
(ALS10) TARDBP; TAR DNA binding protein (mutation) [HSA:23435]
(ALS11) FIG4; FIG4 homolog (mutation) [HSA:9896]
(ALS12) OPTN; optineurin (mutation) [HSA:10133]
NEFH; neurofilament, heavy polypeptide (deletion/insertion in KSP repeat motif) [HSA:4744] [KO:K04574]
PRPH; peripherin (deletion) [HSA:5630] [KO:K07607]
DCTN1; dynactin 1 (mutation) [HSA:1639] [KO:K04648]
MAPT; microtubule-associated protein tau [HSA:4137] [KO:K04380]
Drug
Riluzole [DR:D00775] glutamate release inhibitor
Comment
Affected region: motor cortex, brain stem, spinal cord
Microscopic lesion: hyaline inclusions
Other DBs
Reference
PMID:19251628 (ALS6)
  Authors
Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE
  Title
Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.
  Journal
Science 323:1208-11 (2009)
Reference
PMID:19251627 (ALS6)
  Authors
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr
  Title
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
  Journal
Science 323:1205-8 (2009)
Reference
PMID:19118816 (ALS11)
  Authors
Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, Figlewicz D, Brown RH, Meisler MH
  Title
Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.
  Journal
Am J Hum Genet 84:85-8 (2009)
Reference
PMID:19081518 (drug)
  Authors
Turner MR, Kiernan MC, Leigh PN, Talbot K
  Title
Biomarkers in amyotrophic lateral sclerosis.
  Journal
Lancet Neurol 8:94-109 (2009)
Reference
PMID:18802454 (ALS10)
  Authors
Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L, Rademakers R
  Title
Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral  sclerosis.
  Journal
PLoS Genet 4:e1000193 (2008)
Reference
  Authors
Pasinelli P, Brown RH
  Title
Molecular biology of amyotrophic lateral sclerosis: insights from genetics.
  Journal
Nat Rev Neurosci 7:710-23 (2006)
Reference
  Authors
Gros-Louis F, Gaspar C, Rouleau GA
  Title
Genetics of familial and sporadic amyotrophic lateral sclerosis.
  Journal
Biochim Biophys Acta 1762:956-72 (2006)
Reference
PMID:16501576 (ALS9)
  Authors
Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH Jr, Hardiman O
  Title
ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis.
  Journal
Nat Genet 38:411-3 (2006)
Reference
PMID:15952898 (ALS1)
  Authors
Valentine JS, Doucette PA, Zittin Potter S
  Title
Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.
  Journal
Annu Rev Biochem 74:563-93 (2005)
Reference
PMID:15478096 (ALS4)
  Authors
Kunst CB
  Title
Complex genetics of amyotrophic lateral sclerosis.
  Journal
Am J Hum Genet 75:933-47 (2004)
Reference
  Authors
Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF
  Title
DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).
  Journal
Am J Hum Genet 74:1128-35 (2004)
Reference
  Authors
Julien JP.
  Title
Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.
  Journal
Cell 104:581-91 (2001)
Reference
PMID:20428114 (ALS12)
  Authors
Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H
  Title
Mutations of optineurin in amyotrophic lateral sclerosis.
  Journal
Nature 465:223-6 (2010)

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